tbuckley/cabot-search huggingface dataset:
Abstract 5366: Constructing the largest-scale biomedical knowledge graph using all PubMed articles and its application in automated knowledge discovery
Authors: Yuan Zhang, Feng Pan, Xin Sui, Donghu Sun, Menghan Chung, Jinfeng Zhang
Journal: Cancer Research (2023)

Abstract The number of biomedical publications is growing at an accelerated speed. This ever-increasing amount of scientific literature has made reading all the published articles regularly impossible even for a very specific research area. A solid grasp of existing literature is essential for coming out with novel and plausible scientific ideas. To bridge the gap between the published scientific findings and our incapability of manually processing them, we need to convert the unstructured text into structured form to enable automated methods to use the structured, machine-readable information to generate novel hypotheses, which can then be manually validated. A plausible approach for converting unstructured text into structured form is to use named entity recognition (NER) and relation extraction (RE) methods to identify the biological entities and extract their relations to construct knowledge graphs (KGs). KGs can link concepts within existing research to allow researchers to find connections that may have been difficult to discover without them. The LitCoin Natural Language Processing (NLP) Challenge was recently organized by NCATS of NIH and NASA to spur innovation by rewarding the most creative and high-impact uses of biomedical, publication-free text to create KGs. Our team participated in the challenge and ranked first place. Using the pipelines developed for the LitCoin NLP challenge, we have constructed the largest-scale biomedical KG using all PubMed articles. We further develop advanced deep-learning methods to predict new links from the constructed KG. We demonstrate the power of this new framework using several examples important for drug discovery. Citation Format: Yuan Zhang, Feng Pan, Xin Sui, Donghu Sun, Menghan Chung, Jinfeng Zhang. Constructing the largest-scale biomedical knowledge graph using all PubMed articles and its application in automated knowledge discovery. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5366.
Abstract 1712: Targeting asparagine dependency as a therapy for TP53-mutated castration-resistant prostate cancer
Authors: Young A Yoo
Journal: Cancer Research (2023)

Abstract Background: The TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 gain-of-function (GOF) mutants. Thus, there is an urgent need to identify and target vulnerabilities that perpetuate disease progression and treatment resistance resulting from TP53 GOF mutants. Methods: We performed RNA sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics on GEM and PDX CRPC models with or without TP53 GOF mutations. Our findings were validated using genetic and pharmacologic approaches in relevant in vitro and in vivo models. We assessed the effect of L-asparaginase (ASNase) or/and glutaminase (GLS) inhibitor CB-839 in cell lines, organoids and PDX models. Tumors were characterized by histology and immunohistochemistry for relevant markers. Results: Using transcriptomic and metabolomic analyses, we show here that TP53-mutated prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS, the enzyme catalyzing the synthesis of asparagine). Mechanistically, TP53 GOF mutations transcriptionally activate ASNS expression, directly as well as via ATF4, driving de novo asparagine biosynthesis to support CRPC growth. TP53-mutated CRPC cells are sensitive to asparagine restriction by knockdown of ASNS and L-asparaginase treatment to deplete the intracellular and extracellular sources of asparagine respectively. This effect was rescued by asparagine addition. Notably, pharmacological inhibition of intracellular asparagine biosynthesis using a glutaminase (GLS) inhibitor and depletion of extracellular asparagine with L-asparaginase significantly reduced asparagine production and effectively impaired CRPC growth. Conclusions: This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 GOF mutations, providing a rationale for co-targeting intracellular and extracellular asparagine production to treat these lethal prostate cancers. Citation Format: Young A Yoo. Targeting asparagine dependency as a therapy for TP53-mutated castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1712.
Abstract 6366: NB002, a novel therapeutic antibody targeting unique epitope on TIM-3 presenting potent antitumor activity
Authors: Yu Zhang, Jinyu Dong, Binbin Wang, Jie Ni, Dong Wang, Liegang Shao, Meiguang Xiong, Ting Wang, Florencia McAllister, Xin Dong
Journal: Cancer Research (2023)

Abstract Antibody-based Immune checkpoint inhibitor (ICI) therapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed death receptor-1 (PD-1) have significantly improved clinical outcomes in cancer treatment. Nonetheless, a large portion of the population has limited benefit from these ICI treatments due to lack of efficacy, resistance and intolerance. T-cell immunoglobulin and mucin domain containing-3 (TIM-3) has been proposed as a target for cancer immunotherapy. It is an inhibitory receptor modulating immune tolerance, and its expression has been broadly reported to be closely correlated to T cell exhaustion and pessimistic prognosis. Besides negatively modulating T cell status, TIM-3 is also expressed on natural killer (NK) cells, dendritic cells (DCs), macrophages and regulates immune responses bridging innate immunity and adaptive immunity. NB002 is a novel humanized Fc-engineered IgG1κ antibody, developed via NeologicsBio’s integrated target validation &amp; antibody screening Tier-A platform. It has been characterized in a serial of function and efficacy studies and completed IND-enabling preclinical development. NB002 binds to human TIM3 with high affinity in the low nanomolar range and antagonize the TIM-3 pathway effectively in reporter cell and primary cell assays. NB002 increased the secretion of IFN-γ by activated PBMC cells and enhanced activation and killing activity of NK cells. Moreover, it exhibited a distinctive activity of restoring myeloid cells and enhancing antigen presentation and processing during anti-tumor immune responses, and superior efficacy in multiple humanized mouse models of cancer as monotherapy regimen. Importantly, X-ray crystallography demonstrated that NB002 recognized a unique epitope on TIM-3 and was confirmed by epitope binning assay and structural alignment. These data could potentially explain novel features of NB002, restoring both acquired and innate immunity which could lead cold tumor to hot tumor.In summary, these data showed that NB002 is a potent anti-TIM-3 antibody with pre-clinical properties. A phase 1 study is planned and patients with advanced metastatic solid tumors will be recruited. Citation Format: Yu Zhang, Jinyu Dong, Binbin Wang, Jie Ni, Dong Wang, Liegang Shao, Meiguang Xiong, Ting Wang, Florencia McAllister, Xin Dong. NB002, a novel therapeutic antibody targeting unique epitope on TIM-3 presenting potent antitumor activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6366.
Abstract 3859: Alterations in hormone receptors regulome following response to kinase inhibitors in lethal prostate cancer
Authors: Remi M. Adelaiye-Ogala, Surendra Gulla, Jonathan E. Bard, David J. VanderWeele, Kathleen Kelly
Journal: Cancer Research (2023)

Abstract The androgen receptor (AR) signaling axis is critical for prostate cancer (PCa) pathogenesis and all subsequent phases of disease progression. Although initial success with androgen deprivation therapy and AR-targeted agents such as enzalutamide or abiraterone, most patients inevitably relapse due to therapeutic resistance. Previous studies have shown that genomic AR is unchanged despite resistance to AR antagonists, and its gene expression is unaltered. Therapeutic resistance is broadly classified into two categories; restoration of AR activity and tumor progression despite AR blockade. Indeed, others have noted an extensive reprogramming of the AR cistrome in clinical and preclinical specimens, where a shift in canonical to non-canonical AR cistrome is associated with an increase in Gleason grade. In previous studies, we observed increases in known AR target genes following exposure to kinase inhibitors which was marked by a decrease in tumor growth. We hypothesized that restoration of canonical AR cistrome can be mediated through kinase inhibition and is associated with re-sensitization to AR-targeted therapy. In addition, we treated cell lines and patient-derived xenograft models of advanced prostate cancer with kinase signaling pathway inhibitors, AR signaling inhibitors, or a combination of both for 24 hours (in vitro) or five days (in vivo). In addition, samples were collected and processed for RNA-seq and ChIP-seq. Our transcriptomic analysis showed enrichment of previously published non-canonical AR target genes in cells resistant to AR-targeted agents. When resistant cells were exposed to kinase inhibitors, we observed an enrichment of canonical AR target genes. In addition, we identified unique AR-enriched peaks at active sites associated with resistance. Through GSEA of gene annotated peaks, we found unique regulatory transcription factor targets, some of which are associated with cell proliferation and differentiation and may play a functional role in AR cistrome adaptation to resistance and survival. Overall, our data suggest that AR transcription adapts to the therapeutic resistance of AR antagonists via the enrichment of non-canonical AR cistrome. Furthermore, restoration of canonical AR cistrome is achieved following kinase signaling pathway inhibition and is associated with re-sensitization to AR-targeted therapy. Citation Format: Remi M. Adelaiye-Ogala, Surendra Gulla, Jonathan E. Bard, David J. VanderWeele, Kathleen Kelly. Alterations in hormone receptors regulome following response to kinase inhibitors in lethal prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3859.
Abstract 292: Effects of aqueous cinnamon extract on activity of SIRT1
Authors: William Hrivnak, Khanneth Prak, Cecilia Speck, Courtney Smith, Amy Stockert
Journal: Cancer Research (2023)

Abstract SIRT1 has drawn attention recently due to its involvement in metabolism, aging, and cancer. SIRT1 is a deacetylase enzyme that has the ability to deacetylate histones as well as other non-histone targets including p53. Studies have shown that SIRT can act either as a tumor suppressor or tumor promoter depending on the cancer and its targets in signaling pathways. Recombinant SIRT1 was used to examine the effects of cinnamon extract on SIRT1 activity using the Epigenase(™) Universal SIRT activity/Inhibition Assay Kit. Here we demonstrate that under conditions of acidic extraction, cinnamon extract functions as an activator of SIRT1 activity. Under conditions of non-acidic extraction, SIRT1 activity was relatively unchanged and slightly reduced. Studies have suggested that polyphenolic compounds, like those found in cinnamon, may epigenetically affect MCF7 cells. Therefore our future work includes plans to determine if cinnamon extracted under acidic conditions alters the expression level of SIRT1. SIRT1 activity will also be examined following cinnamon extract pretreatment. Citation Format: William Hrivnak, Khanneth Prak, Cecilia Speck, Courtney Smith, Amy Stockert. Effects of aqueous cinnamon extract on activity of SIRT1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 292.
Abstract 63: Machine learning identifies experimental brain metastasis subtypes based on their influence on neural circuits
Authors: Mariam Masmudi-Martín, A Sanchez-Aguilera, A Navas-Olive, P Baena, C Hernández-Oliver, S Martínez, M Lafarga, Renacer Red Nacional de Metástasis Cerebral, MZ Lin, L Menendez de la Prida, M Valiente
Journal: Cancer Research (2023)

Abstract A high percentage of patients with brain metastases frequently develop neurocognitive symptoms, however understanding how brain metastasis co-opt the function of neuronal circuits beyond a mass effect remains unknown. We report a comprehensive multidimensional modelling of brain functional analysis in the context of brain metastasis. By testing different pre-clinical models of brain metastasis from various primary sources and oncogenic profiles we dissociated the heterogeneous impact on brain function that we detected from the homogeneous inter-model tumor size or glial response. In contrast we report a potential underlying molecular program responsible for impairing neuronal crosstalk in a model-specific manner. Additionally, measurement of various brain activity readouts matched with machine learning strategies confirmed model-specific alterations that could help to predict the presence and subtype of metastasis. Citation Format: Mariam Masmudi-Martín, A Sanchez-Aguilera, A Navas-Olive, P Baena, C Hernández-Oliver, S Martínez, M Lafarga, Renacer Red Nacional de Metástasis Cerebral, MZ Lin, L Menendez de la Prida, M Valiente. Machine learning identifies experimental brain metastasis subtypes based on their influence on neural circuits [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 63.
Abstract 6320: CUSP06/AMT-707, a new CDH6-targeting antibody-drug conjugate, demonstrates potent antitumor activity in preclinical models
Authors: Wei Lu, Jing Shi, Shu-Hui Liu, Nicole Covino, Xun Meng, Eric D. Slosberg
Journal: Cancer Research (2023)

Abstract Cadherin-6 (CDH6), also known as K-cadherin, is a type II classic cadherin molecule that plays an important role in the embryonic development of the kidney, but has very limited expression in adult tissues. It is overexpressed in several human malignancies, primarily in ovarian, renal, but also (to a lesser degree) gastric, thyroid, cholangiocarcinoma and other tumor types. The characteristics of limited expression in normal tissues, high expression in tumor tissues, and rapid internalization upon antibody binding makes CDH6 a well-suited Antibody-drug Conjugate (ADC) target. We developed a novel CDH6-targeting ADC, CUSP06, consisting of a proprietary humanized antibody selective for CDH6, a protease cleavable linker, and an exatecan payload, with a drug-to-antibody ratio (DAR) of 8. CUSP06 selectively bound to cell surface CDH6 and was efficiently internalized into CDH6 positive ovarian and renal cancer cells. CUSP06 exhibited strong antiproliferative activity against several CDH6 positive cancer cell lines in vitro. Furthermore, compared to a DXd-based ADC, a exatecan-based ADC demonstrated improved bystander effect. Treatment with CUSP06 resulted in tumor regression in several CDH6 positive cell line derived xenograft (CDX) models, including PA-1, OVCAR3, and 786-O. In addition, CUSP06 demonstrated potent antitumor activity with tumor regression observed in two CDH6 low and high expressing patient derived xenograft (PDX) models. The preclinical activity of CUSP06 against CDH6-expressing tumors provide compelling support for the clinical development of CUSP06 in CDH6-expressing human cancers. CUSP06 is currently in IND-enabling studies. CUSP06 showed an expected toxicity profile consistent with it's exatecan payload in the ongoing pilot toxicology studies. We plan to initiate a Phase 1 first-in-human clinical trial in the 2nd half of 2023. Citation Format: Wei Lu, Jing Shi, Shu-Hui Liu, Nicole Covino, Xun Meng, Eric D. Slosberg. CUSP06/AMT-707, a new CDH6-targeting antibody-drug conjugate, demonstrates potent antitumor activity in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6320.
Abstract 6633: T regulatory cell subsets in colorectal cancer: friends or foes
Authors: Eyad Elkord
Journal: Cancer Research (2023)

Abstract T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity. Different T cell subsets may have opposing roles in tumor progression, especially in inflammatory cancers such as colorectal cancer (CRC). In different series of studies, we performed extensive characterization and critical analyses of T regulatory cell (Treg)-related markers and key inhibitory immune checkpoints (ICs) in CD4+ and CD8+ T cell subsets in the TME and periphery of CRC patients. We found a significant increase in levels of CD4+FoxP3+Helios+ T cells, which represent potentially highly immunosuppressive Tregs, in the TME. Additionally, tumor-infiltrating CD4+ T cells upregulated PD-1, CTLA-4, TIM-3 and LAG-3 immune checkpoints. CTLA-4, TIM-3, and LAG-3 were mainly co-expressed on FoxP3+Helios+ Tregs in the TME. Additionally, we found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in tumor-infiltrating CD8+ T cells. We then investigated associations between different tumor-infiltrating CD4+ and CD8+ T cell subpopulations and disease-free survival (DFS). Interestingly, a high frequency of circulating CD4+FoxP3+ Tregs was associated with poorer DFS, while higher frequency of these cells in the TME was associated with better DFS. Additionally, high frequencies of circulating CD4+FoxP3+Helios+ Tregs and tumor-infiltrating CD4+FoxP3-Helios- T cells were associated with poorer DFS. Moreover, a high frequency of CD4+FoxP3+Helios-PD-1+ Tregs in circulation was associated with worse DFS. In contrast, high frequencies of CD4+TIM-3+ T cells, FoxP3+Helios+TIM-3+ Tregs, and FoxP3-Helios+TIM-3+ CD4+ T cells in circulation were associated with longer DFS. Additionally, we found that high levels of certain circulating CD8+ T cell subsets (TIM-3+, FoxP3-Helios-TIM-3+ and FoxP3-Helios+TIM-3+ cells) were associated with longer DFS. In the TME, elevated levels of CD25+ and TIM-3+ CD8+ T cells, and FoxP3+Helios-TIM-3+ CD8+ Tregs were associated with better DFS. These data show that circulating and tumor-infiltrating immune checkpoint-expressing CD4+ and CD8+ Treg/T cell subsets play different roles in disease prognoses, and certain subsets could serve as independent predictive biomarkers in CRC patients. Citation Format: Eyad Elkord. T regulatory cell subsets in colorectal cancer: friends or foes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6633.
Abstract 1027: Assessment of tumor mutation burden (TMB) based on whole exome sequencing using extracellular vesicles-derived DNA obtained from bronchoalveolar lavage fluid (BALF) in advanced NSCLC patients treated with pembrolizumab
Authors: Heejoung Kim, Jaeyoung Hur, Wan Seop Kim, In Ae Kim, Dong Il Park, In-Jae Oh, Kye Young Lee
Journal: Cancer Research (2023)

Abstract Background: Although multiple immune checkpoint inhibitors showed improved outcomes in patients with high tumor mutational burden (TMB) as well as high PD-L1 expression, obtaining adequate tumor tissue for various molecular testing including next-generation sequencing (NGS) is not a simple issue in patients with advanced non-small cell lung cancer (NSCLC). We aimed to assess TMB based on whole exome sequencing (WES) using extracellular vesicles (EV)-derived DNA isolated from bronchoalveolar lavage fluid (BALF) and determine the correlation of TMB between BALF and tissue. Methods: Patients diagnosed with advanced NSCLC and who were treated with pembrolizumab between December 2018 and December 2021 were included in this multicenter translational cohort study. The correlation of TMB between BALF and tissue measured by WES was evaluated by Spearman’s rank correlation coefficient in matched BALF and tissue samples from 62 patients. We analyzed the association of BALF TMB level with progression-free survival (PFS) and response to pembrolizumab. Results: Of 62 patients, 47 (75.8%) had evaluable tissue TMB and 57 (91.9%) had evaluable BALF TMB. There were no significant differences between BALF and tissue with regards to DNA amounts, estimated library size, mean depth, and uniformity. Median tissue TMB and BALF TMB were 6.02 and 2.16 mut/Mb, respectively. There was a weak positive correlation between tissue TMB and BALF TMB (r=0.23, p &amp;lt; 0.001), whereas BALF TMB found higher correlations with tissue TMB in patients with squamous cell carcinoma (r=0.77, p &amp;lt; 0.001). Neither tissue TMB nor BALF TMB showed significant differences PFS or ORR benefit for treatment with pembrolizumab, however the BALF TMB of patients who had been treated with pembrolizumab for more than 6 months was higher than that of those who did not (p=0.039). Conclusions: The findings suggest that NGS using BALF EV DNA is feasible for TMB calculation to overcome the matter of small biopsy issue in advanced NSCLC patients, which may play a supplementary serve as a potential biomarker of clinical benefit in patients with NSCLC treated with pembrolizumab. Citation Format: Heejoung Kim, Jaeyoung Hur, Wan Seop Kim, In Ae Kim, Dong Il Park, In-Jae Oh, Kye Young Lee. Assessment of tumor mutation burden (TMB) based on whole exome sequencing using extracellular vesicles-derived DNA obtained from bronchoalveolar lavage fluid (BALF) in advanced NSCLC patients treated with pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1027.